ACNE FULMINAN

Background
Acne fulminans (AF), also known as acne maligna, was originally described as acute febrile ulcerative acne conglobata (AC). In 1958, at a meeting of the Detroit Dermatological Society, Burns and Colville presented a 16-year-old white boy with acute febrile disease and acne conglobata. Many similar cases have been reported since then.[1] The primary features of this disease include sudden onset, severe and often ulcerating acne, fever, polyarthritis,[2] and failure to respond to antibacterial therapy; the response to debridement in combination with steroid therapy is good. It can be the dermatologic manifestation of the synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome.[3] Acne fulminans is a syndrome of fulminant, necrotizing acne associated with bone lesions, constitutional symptoms, and laboratory abnormalities.

Pathophysiology
Acne fulminans is an uncommon, immunologically induced, systemic disease in which the triggering antigen is believed to be from Propionibacterium acnes. Some authors note that elevated blood levels of testosterone may play an important role in the pathogenesis of acne fulminans. High levels of testosterone and anabolic steroids cause an increase in sebum excretion and in the population density of P acnes. The trigger for acne induction seemed to be a testosterone therapy in a patient with Marfan syndrome.[4] The increase in the amount of P acnes or related antigens may trigger the immunologic reaction in some individuals and lead to an occurrence of acne fulminans.[5] In addition to testosterone, isotretinoin may also precipitate acne fulminans, possibly related to highly increased levels of P acnes antigens in the patient's immune system.[6] Another theory postulates that acne fulminans may be an autoimmune complex disease because circulating immune complexes have been demonstrated in some patients with acne fulminans. Immunologically, the reaction is a type III or IV hypersensitivity reaction. Genetic factors may play an important role in some patients; 4 sets of identical twins who developed an identical pattern of acne fulminans have been documented.[7] Acne may be the only clinical sign of androgen excess in men, and one report is available about a boy with acne fulminans and androgen excess due to late-onset congenital adrenal hyperplasia.[8] Acne fulminans has also been observed in patients with measles infection.

History
The primary features of this disease include the following: Sudden onset Severe and often ulcerating acne Fever and polyarthritis Failure to respond to antibacterial therapy Good response to oral steroid therapy, after 4-6 weeks, the addition of oral isotretinoin Acne fulminans predominantly affects young males with a history of acne. Painful splenomegaly and erythema nodosum may be present.[11] Bone pain related to aseptic osteolysis may be present. Gordon et al report a case of a 13-year-old boy with severe acne and multiple osteolytic bone lesions who presented to pediatric oncologists; the patient avoided unnecessary painful diagnostic procedures when it was recognized he had acne fulminans.[12] Patients with acne fulminans and acneiform folliculitis may have chronic aseptic multifocal osteomyelitis.

Physical
Acne fulminans (similar to acne conglobata) demonstrates numerous inflammatory nodules on the trunk. In acne fulminans, the large nodules tend to become painful ulcers with overhanging borders surrounding exudative necrotic plaques that become confluent; however, polyporous comedones and noninflammatory cysts are not evident (as seen in acne conglobata). Erythematous neovascular nodules may also be seen. Acne fulminans is a systemic disease. Patients may demonstrate a bent-over posture because polyarthritis may make walking painful. Inflammatory arthralgia may affect 1 joint or several joints, especially the hips, the knees, and the thighs.

Differentials
Acne Conglobata Acne Vulgaris Acneiform Eruptions Pyoderma Gangrenosum

Laboratory Studies
Findings in patients with acne fulminans include the following: Leukocytosis (characteristic finding)

 Increased percentage of polymorphonuclear leukocytes Anemia Leukemic-type reaction Elevated erythrocyte sedimentation rate Circulating immune complexes Proteinuria Sterile blood culture results

Imaging Studies
Bone involvement is common. Approximately 50% of patients have lytic bone lesions demonstrated on radiographs, and 70% of patients show increased uptake using technetium scintillography ("hot spots"). Destructive lesions resembling osteomyelitis are demonstrated on radiographs in 25% of patients. Multifocal osteolytic cysts may be evident as tender bones and can be detected as hot spots by technetium scintillography.

Oral Steroids and Isotretinoin

The recommended treatment for acne fulminans is a combination of oral steroids and isotretinoin.[13, 14, 15] Oral steroids should be started and gradually reduced over 6 weeks to avoid adverse effects of a prolonged course of systemic steroids. Isotretinoin should be started at 4 weeks, initially at 0.25 mg/kg daily and gradually increased to achieve complete clearance. Isotretinoin with a minimum total dose of 120 mg/kg is recommended. Relapses are rare. If required, a repeat course of isotretinoin (150 mg/kg) may be used. Suicidal ideation, a concern in seemingly healthy adolescents, should be anticipated in those with cosmetically disturbing skin disorders, such as AF. Some believe that isotretinoin may exacerbate this tendency. Some authors suggest treating patients with spontaneous development of acne fulminans with oral steroids and supplemental intralesional therapy. The response to broad-spectrum antibiotic treatment is poor. Oral antibiotics are responsible for a slow response in the resolution of acne and systemic symptoms. The combination of oral isotretinoin and systemic steroids is better than the combination of oral isotretinoin and antibiotics. Infliximab, a monoclonal antibody against tumor necrosis factor-alpha, also may be a treatment option for patients with AF that is unresponsive

to conventional therapies. Other treatment Friedlander reported that the pulsed dye laser is effective treatment for acne fulminansassociated granulation tissue.

Medication Summary
Begin treatment with oral prednisone 1 mg/kg/d and taper over 6 weeks. By the fourth week, initiate isotretinoin at 0.25 mg/kg/d. If isotretinoin cannot be used, dapsone may be substituted for the retinoid, beginning at 50 mg/d and increasing to 100-150 mg/d. Prednisone (Delta-Cortef, Econopred) Synthetic adrenocortical steroid with predominantly glucocorticoid properties. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production. Isotretinoin (Accutane) Oral agent that treats serious dermatologic conditions. Isotretinoin is the synthetic 13-cis isomer of the naturally occurring tretinoin (trans -retinoic acid). Both agents are structurally related to beta-carotene. Decreases sebaceous gland size and sebum production. May inhibit sebaceous gland differentiation and abnormal keratinization. Dosing Forms & Strengths capsule 10mg 20mg 30mg 40mg Severe Recalcitrant Nodular Acne Initial: 0.5-1 mg/kg/d, THEN 0.5-2 mg/kg/d PO divided BID for 15-20 wk Prescribers require registration in iPledge, an FDA-approved risk management program designed to minimize pregnancy exposures to isotretinoin (enhancement of earlier riskMAP) Tretinoin topical (Avita, Retin-A, Retin-A Micro) Structurally related to vitamin A. May be helpful for recalcitrant disease, but recurrence is common. Long-term, low-dose therapy may be

suitable for selected patients. May cause skin irritation in some patients. Also, has been linked to promotion of angiogenesis; however, has not demonstrated increased telangiectasias. Also inhibits microcomedo formation and eliminates lesions. Makes keratinocytes in sebaceous follicles less adherent and easier to remove. Available as 0.025%, 0.05%, and 0.1% creams. Available also as 0.01% and 0.025% gels. Class Summary Vitamin A derivatives have many roles. They encourage cellular differentiation, are antiproliferative, and serve as immunomodulators. A US Food and Drug Administrationmandated registry is now in place for all individuals prescribing, dispensing, or taking isotretinoin. For more information on this registry, see iPLEDGE. This registry aims to further decrease the risk of pregnancy and other unwanted and potentially dangerous adverse effects during a course of isotretinoin therapy. Suicidal ideation, a concern in seemingly healthy adolescents, should be anticipated in those with cosmetically disturbing skin disorders, such as acne fulminans. Some believe that isotretinoin may exacerbate this tendency.

Sulfone antibiotics
Class Summary These agents may inhibit bacterial growth by preventing the formation of folic acid. Dapsone (Avlosulfon) Bactericidal and bacteriostatic against Mycobacteria species; mechanism of action is similar to that of sulfonamides in which competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth. Anti-inflammatory mechanism of action may involve suppression of neutrophil function by inhibition of the halidemyeloperoxidase system. Excretion is primarily in urine; half-life is 28 h